Transforming growth factors, including TGF-β, play a key role in controlling cellular functions such as proliferation, differentiation, migration, extracellular matrix production, apoptosis, adhesion, and development. Deregulated TGF-β signaling has been identified as a key factor in a number of pathological disorders.
TGF-β and other cyctokines signal through a complex of two structurally and functionally distinct transmembrane receptor serine/threonine kinases, known as type I and type II TGF-β receptors, resulting in activation of TGF-β mediated pathways. The type I TGF-β receptor is also known as activin-like kinase 5 (ALK5). Inhibition of ALK5 antagonizes TGF-β mediated pathways and provides diverse biological effects in clinical applications, including the treatment of cancer, fibrosis, cardiovascular disorders, wound healing, and many others.
Certain inhibitors of ALK5 are disclosed in WO 2004/065392, WO 2009/050183, and WO 2009/133070. The present invention provides inhibitors of ALK5.